The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament which particularly acts on the central nervous system.
Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. A number of pharmacological and genetic experiments involving receptors for serotonin strongly implicate the 5-HT2c receptor subtype in the regulation of food intake (Obes. Res. 1995, 3, Suppl. 4, 449S-462S). The 5-HT2c receptor subtype is transcribed and expressed in hypothalamic structures associated with appetite regulation. It has been demonstrated that the non-specific 5-HT2c receptor agonist m-chlorophenylpiperazine (mCPP), which has some preference for the 5-HT2c receptor, causes weight loss in mice that express the normal 5-HT2c receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2c receptor (Nature 1995, 374, 542-546). In a recent clinical study, a slight but sustained reduction in body weight was obtained after 2 weeks of treatment with mCPP in obese subjects (Psychopharmacology 1997, 133, 309-312). Weight reduction has also been reported from clinical studies with other xe2x80x9cserotonergicxe2x80x9d agents (see e.g. IDrugs 1998, 1, 456-470). For example, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptake inhibitor dexfenfluramine have exhibited weight reduction in controlled studies. However, currently available drugs that increase serotonergic transmission appear to have only a moderate and, in some cases, transient effects on the body weight.
The 5-HT2c receptor subtype has also been suggested to be involved in CNS disorders such as depression and anxiety (Exp. Opin. Invest. Drugs 1998, 7, 1587-1599; IDrugs, 1999, 2, 109-120).
The 5-HT2c receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (IDrugs, 1999, 2, 109-120).
Compounds which have a selective effect on the 5-HT2c receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above. Of course, selectivity also reduces the potential for adverse effects mediated by other serotonin receptors.
U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorectic agent.
EP-A1-863 136 discloses azetidine and pyrrolidine derivatives which are selective 5-HT2c receptor agonists having antidepressant activity and which can be used for treating or preventing serotonin-related diseases, including eating disorders and anxiety.
EP-A-657 426 discloses tricyclic pyrrole derivatives having activity on the 5-HT2c receptor and which inter alia may be used for treating eating disorders.
EP-A-655 440 discloses 1-aminoethylindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
EP-A-572 863 discloses pyrazinoindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
J. Med. Chem. 1978, 21, 536-542 and U.S. Pat. No. 4,081,542 disclose a series of piperazinylpyrazines having central serotonin-mimetic activity.
J. Med. Chem. 1981, 24, 93-101 discloses a series of piperazinylquinoxalines with central serotoninmimetic activity.
WO 00/12475 discloses indoline derivatives as 5-HT2b and/or 5-HT2c receptor ligands, especially for the treatment of obesity.
WO 00/12510 discloses pyrroloindoles, pyridoindoles and azepinoindoles as 5-HT2c receptor agonists, particluarly for the treatment of obesity.
WO 00/12482 discloses indazole derivatives as selective, directly active 5-HT2c receptor ligands, preferably 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/12502 discloses pyrroloquinolines as 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/12475 discloses indoline derivatives as 5-HT2b and/or 5-HT2c receptor ligands, especially for the treatment of obesity.
GB-B-1,457,005 discloses 1-piperazinyl-2-[2-(phenyl)ethenyl]-quinoxaline derivatives which exhibit anti-inflammatory activity.
Chem. Pharm. Bull. 1993, 41(10) 1832-1841 discloses 5-HT3 antagonists including 2-(4-methyl-1-piperazinyl)-4-phenoxyquinoxaline.
GB-B-1,440,722 discloses 2-(1xe2x80x2-piperazinyl)-quinoxaline compounds having pharmaceutical activity against depression.
WO 96/11920 discloses CNS-active pyridinylurea derivatives.
WO 95/01976 discloses indoline derivatives active as 5-HT2c antagonists and of potential use in the treatment of CNS disorders.
WO 97/14689 discloses aryl-piperazine cyclic amine derivatives which are selective 5-HT1d receptor antagonists.
WO 98/42692 discloses piperazines derived from cyclic amines which are selective antagonists of human 5-HT1a, 5-HT1d and 5-HT1b receptors.
GB-B-1,465,946 discloses substituted pyridazinyl, pyrimidinyl and pyridyl compounds which are active as P-receptor blocking agents.
EP-A-711757 discloses [3-(4-phenyl-piperazin-1-yl)propylamino]-pyridine, pyrimidine and benzene derivatives as xcex1-adrenoceptor antagonists.
WO 99/03833 discloses aryl-piperazine derivatives which are 5-HT2 antagonists and 5-HT1a receptor agonists and therefore are useful as remedies or preventives for psychoneurosis.
WO 96/02525 discloses aryl-piperazine-derived piperazide derivatives having 5-HT receptor antagonistic activity.
WO 99/58490 discloses aryl-hydronaphthalen-alkanamines which may effectuate partial or complete blockage of serotonergic 5-HT2c receptors in an organism.
According to the present invention, a class of novel compounds have been developed which bind to the 5-HT2c receptor (agonists and antagonists) and which therefore may be used for the treatment of serotonin-related disorders.
In one aspect, the invention provides novel compounds of the general formula (I): 
wherein
Ar is aryl or heteroaryl which may be independently substituted in one or more positions by C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-acyl, C1-6-alkylsulphonyl, cyano, nitro, hydroxy, C2-6-alkenyl, C2-6-alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, halogen, xe2x80x94N(R2)(R3), aryl, aryloxy, arylthio, aryl-C1-4-alkyl, aryl-C2-4-alkenyl, aryl-C2-4-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio or heterocyclyl-C1-4-alkyl, wherein any aryl and heterocyclyl residues as substituents or part of substituents on aryl or heteroaryl in turn may be substituted in one or more positions independently of each other by halogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-acyl, C1-6-alkylsulphonyl, nitro, trifluoromethyl, trifluoromethylthio, cyano, hydroxy, amino, C1-6-alkylamino, di(C1-6-alkyl)amino or C1-6-acylamino;
A is (i) xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94or xe2x80x94NHxe2x80x94; (ii) a C1-4-alkyl-substituted nitrogen atom, or (iii) a C1-8-alkylene chain or a heteroalkylene chain having 2 to 8 chain atoms, which optionally contains one or more unsaturations, wherein C1-8-alkylene and heteroalkylene may be independently substituted in one or more positions by C1-4-alkyl or oxo, and wherein two juxtaposed or spaced chain atoms in C1-8-alkylene or heteroalkylene optionally are joined through an alkylene bridge having 1 to 5 chain carbon atoms or a heteroalkylene bridge having 2 to 5 chain atoms, or two spaced chain atoms in C1-8-alkylene or heteroalkylene optionally are joined through a bridging bond, to form a saturated or partially or fully unsaturated carbocyclic or heterocyclic ring having 3 to 8 ring members;
B is xe2x80x94C(R4)(R5)xe2x80x94, xe2x80x94OC(R4)(R5)xe2x80x94, xe2x80x94N(R6)C(R4)(R5)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94or xe2x80x94SO2xe2x80x94;
R is C3-8-cycloalkyl, aryl or heteroaryl, each of which may be substituted in one or more positions independently of each other by C1-6-alkyl, C1-6-alkoxy, fluoro-C1-6-alkoxy, 2,2,2-trifluoroethoxy, C3-5-alkynyloxy, C3-5-alkenyloxy, dimethylamino-C1-6-alkoxy, methylamino-C1-6-alkoxy, C1-6-alkylthio, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethylthio, difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, trifluoromethylsulphonyloxy, C1-6-alkylsulphonamido, C2-6-alkenyl, C2-6-alkynyl, C1-6-acyl, C1-6-alkylcarbonyl-C1-6-alkyl, C1-6-alkylsulphonyl, C1-6-alkylsulphonyloxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxycarbonyl, C1-6-alkoxycarbonyl-C1-6-alkyl, C1-6-acyloxy-C1-6-alkyl,hydroxy-C1-6-alkyl, hydroxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkylthio, hydroxy-C1-6-alkylthio, heteroaryl-C1-6-alkylthio, aryl-C1-6-alkylthio, C1-6-alkoxy-C1-6-alkylamino, N-(C1-6-alkoxy-C1-6-alkyl)-N-methylamino, C3-6-cycloalkyl-C1-6-alkoxy, aryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyloxy, aryl, aryloxy, arylthio, arylsulphonyl, aryl-C1-6-acyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylsulphonyl, heterocyclylamino, heterocyclyl-C1-6-acyl, xe2x80x94N(R2)(R3), xe2x80x94CON(R7)(R8) or, when R is optionally substituted C3-8-cycloalkyl, oxo, wherein any 20 cycloalkyl, aryl and heterocyclyl residues as substituents on C3-8-cycloalkyl, aryl or heteroaryl or as part of substituents on C3-8-cycloalkyl, aryl or heteroaryl in turn may be substituted in one or more positions independently of each other by C1-4-alkyl, C1-4-alkoxy, methanesulphonamido, C1-4-alkylthio, C1-4-alkylsulphonyl, C1-4-acyl, heterocyclyl, heterocyclyloxy, heterocyclylthio, aryloxy, arylthio, fluoromethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, N(R2)(R3) or, for C3-8-cycloalkyl and partially or fully saturated heterocyclyl, oxo or hydroxy;
R1 is (i) a saturated or unsaturated azacyclic or aminoazacyclic ring, or a saturated diazacyclic or aminodiazacyclic ring, which has 4 to 7 ring members, or a saturated aminoazabicyclic, azabicyclic or diazabicyclic ring which has 7 to 10 ring members, which mono- or bicyclic rings may be mono- or disubstituted in one or more positions independently of each other by, preferably bound to a carbon atom, C1-4-alkyl, C1-4-alkoxy, fluoromethyl, trifluoromethyl, difluoromethyl, hydroxymethyl or methoxymethyl or -N(R6)2, or, preferably bound to a ring nitrogen atom, hydroxy, 2-hydroxyethyl or 2-cyanoethyl, or, bound to a ring nitrogen atom, C1-6-acyl, C1-4-alkoxycarbonyl or tetrahydropyran-2-yl, and wherein a saturated azacyclic ring may contain a further heteroatom selected from oxygen and sulphur; or (ii) a group xe2x80x94[C(R4)(R5)]xN(R2a)(R3a);
R2 and R3 independently of each other are hydrogen, C1-6-alkyl, C1-6-acyl, xe2x80x94CON(R7)(R8), aryl, heterocyclyl, aryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-acyl or heterocyclyl-C1-6-acyl, wherein any aryl and heterocyclyl residues in turn may be substituted in one or more positions independently of each other by halogen, C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or xe2x80x94N(R2)(R3); or R2 and R3 together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members and optionally containing a further heteroatom, which ring may be substituted by C1-6-alkyl, C1-6-alkoxy, oxo or hydroxy;
R2a and R3a independently of each other are hydrogen, methyl or ethyl, or R2a and R3a together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine, morpholine, thiomorpholine or piperidine ring;
R4 and R5 independently of each other, and independently on each substituted carbon atom, are hydrogen or C1-6-alkyl;
R6 is hydrogen or C1-6-alkyl;
R7 and R8 independently of each other are hydrogen, C1-6-alkyl, aryl, heteroaryl, aryl-C1-4-alkyl or heteroaryl-C1-4-alkyl, wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by halogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio or xe2x80x94N(R2)(R3); or R7 and R8 together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members and optionally containing a further heteroatom;
n is 0 or 1, and
x is 2, 3 or 4; with the proviso that (i) when xe2x80x94Axe2x80x94R is phenoxy or phenylthio, then Ar is other than quinoxalinyl or pyridyl, and (ii) when A is ethenylene, then Ar is other than quinoxalinyl;
and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
A limited group of compounds of the invention comprise compounds of formula (I) as defined above but with the further proviso that when Ar is optionally substituted phenyl, pyridyl or quinoxalinyl, then A is a group xe2x80x94Hetxe2x80x94CH(R6)xe2x80x94CH(R6)xe2x80x94Hetxe2x80x94, where each Het independently is selected from O, S and N(R6), and R6 is as defined above.
In case the compounds of formula (I) can be in the form of optical isomers, the invention comprises the racemic mixture as well as the individual enantiomers as such.
In case the compounds of formula (I) contain groups which may exist in tautomeric forms, the invention comprises the tautomeric forms of the compounds as well as mixtures thereof, e.g. a 2-hydroxypyridine and its tautomer 1H-2-pyridone.
In case the compounds of formula (I) can be in the form of geometrical isomers, the invention comprises the geometrical isomers as well as mixtures thereof.
In another aspect, the invention provides the compounds according to formula (I) above for use in therapy.
Still another aspect of the invention provides a pharmaceutical composition comprising a compound according to formula (I) above as the active ingredient, preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.
In yet another aspect, the invention provides a method for the treatment of a human or animal subject suffering from a serotonin-related disease, particularly 5-HT2 receptor-related, especially eating disorders, particularly obesity; memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders.
Another aspect of the invention provides the use of the compounds according to formula (I) above for the manufacture of a medicament for the treatment of a serotonin-related disease, particularly 5-HT2 receptor-related, especially eating disorders, particularly obesity; memory disorders; schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders.
Still another aspect of the invention provides methods for the preparation of the compounds according to formula (I) above.
First, the various terms used, separately and in combinations, in the above definition of the compounds having the general formula (I) will be explained.
By xe2x80x9cheteroatomxe2x80x9d is meant nitrogen, oxygen, sulphur, and in heterocyclic rings (including heteroaromatic as well as saturated and partially saturated heterocyclic rings), also selenium.
The term xe2x80x9carylxe2x80x9d is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl, naphthyl and 1,2,3,4-tetrahydronaphthyl (substitutions may be in any ring).
The term xe2x80x9cheteroarylxe2x80x9d means a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic, and substitutions may be in any ring) having from 5 to 14, preferably 5 to 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur, oxygen and selenium. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, coumarin, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, 2,3-dihydro-1,4-benzodioxine, indane, 1,3-benzodioxole, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine, acridine, fenazine, xanthene, 3,4-dihydro-2H-pyrido[3,2-b]-1 ,4-oxazine, and 2,3-dihydro-1,4-benzoxathiine. The heteroaryl ring may be linked to the divalent group A in formula (I) via a carbon or nitrogen atom thereof. If a bi- or tricyclic ring is substituted, it may be substituted in any ring.
The term xe2x80x9cheteroalkylenexe2x80x9d means an alkylene group which contains a terminal heteroatom at one or both ends and/or one or more carbon chain-interrupting heteroatom(s) selected from N, O and S. The number of heteroatoms is at least one, and usually from one to three, especially one or two. When heteroalkylene is substituted, it is usually substituted at a carbon atom by C1-4-alkyl or oxo, but it may alternatively or additionally be substituted at a nitrogen by C1-4-alkyl or at a sulphur atom by oxo (Sxe2x95x90O or Oxe2x95x90Sxe2x95x90O), if present.
The term xe2x80x9cheterocyclylxe2x80x9d is intended to include fully unsaturated (i.e. aromatic) as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms, and containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, such as, for example, the heteroaryl groups mentioned above as well as their corresponding partially saturated or fully saturated heterocyclic rings. Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.
C1-6-alkyl, which may be straight or branched, is preferably C1-4-alkyl. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.
C1-6-alkoxy, which may be straight or branched, is preferably C1-4-alkoxy. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy.
C2-6-alkenyl, which may be straight or branched, is preferably C2-4-alkenyl, e.g. 1-propenyl, 2-propenyl, vinyl.
C2-6-alkynyl, which may be straight or branched, is preferably C2-4-alkynyl, e.g. propargyl, ethynyl.
C3-8-cycloalkyl is preferably C4-7-cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
C1-6-acyl may be saturated or unsaturated and is preferably C1-4-acyl. Exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3-butenoyl), hexenoyl (e.g. 5-hexenoyl).
C1-8-alkylene (wherein 1-8 is the number of chain carbon atoms) and heteroalkylene having 2 to 8 chain atoms, which may contain one or more unsaturations (double and/or triple bonds), are preferably C1-4-alkylene and heteroalkylene of 2 to 4 chain atoms, respectively. Exemplary alkylene groups include methylene, ethylene, propylene, butylene and their isomers (e.g. 1,3-butylene, 2-methyl-1,3-propylene). Exemplary heteroalkylene groups include oxymethylene (and methylenoxy), oxyethylene (and ethylenoxy), oxypropylene (and propylenoxy), oxybutylene (and butylenoxy), ethylenedioxy, propylenedioxy, butylenedioxy, oxyallyl (and allyloxy), etc. An exemplary alkyl-substituted heteroalkylene group is methylethylenedioxy.
Hydroxy-C1-6-alkyl may be straight or branched. Exemplary hydroxyalkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.
Exemplary aryl-C1-6-acyl groups include benzoyl, 1-naphthoyl, 2-naphthoyl, cinnamoyl and phenylacetyl.
Exemplary C1-6-alkylcarbonyl-C1-6-alkyl groups include 2-oxobutyl.
Exemplary C1-6-alkoxy-C1-6-alkyl groups include 2-ethoxyethyl.
Exemplary C1-6-alkoxycarbonyl-C1-6-alkyl groups include ethoxycarbonylbutyl.
Exemplary C1-6-acyloxy-C1-6-alkyl groups include propanoyloxypropyl.
Exemplary saturated and unsaturated (partially and fully) azacyclic and saturated azabicyclic rings include azetidine, pyrrolidine, piperidine, morpholine, hexahydroazepine, tetrahydropyridine, pyridine and 1-azabicyclo [2.2.2] octane. The azacyclic and azabicyclic rings are coupled via a ring carbon atom when n =0.
Exemplary saturated and unsaturated aminoazacyclic rings include aminopiperidine (e.g. 4-aminopiperidine), aminoazetidine (e.g. 3-aminoazetidine), aminopyrrolidine (e.g. 3-aminopyrrolidine), and aminopyridine (e.g. 4-aminopyridine). The aminoazacyclic rings are preferably coupled to B or Ar in formula (I) via either the aza nitrogen atom or the amino nitrogen atom. An example of a saturated aminoazabicyclic ring is 3-aminoazabicyclo[2.2.2]octane, and the coupling is preferably via the 3-amino nitrogen atom.
An example of a saturated aminodiazacyclic ring is 1-aminopiperazine, and the coupling is preferably via either the 4-aza nitrogen atom or the 1-amino nitrogen atom.
Exemplary saturated diazacyclic rings include piperazine and homopiperazine, and an example of a diazabicyclic ring is diazabicyclo[2.2.1]heptane. The diazacyclic and diazabicyclic rings are preferably coupled via one of the ring nitrogens.
The group -[C(R4)(R5)]xN(R2a)(R3a) is preferably linked to Ar in formula (I) via a heteroatom (i.e. when n=1 and B is oxygen, nitrogen or sulphur).
As indicated by the expression xe2x80x9cindependently for each substituted carbon atomxe2x80x9d with regard to substituents R4 and R5, each individual carbon atom in the chain xe2x80x94[C(R4)(R5)]xxe2x80x94 may be differently substituted than the adjacent carbon atom(s). An exemplary chain, wherein x=3, illustrating this is xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94C(CH3)(CH3)xe2x80x94.
Halogen includes fluorine, chlorine, bromine and iodine.
Where it is stated above that aryl, heteroaryl and heterocyclyl residues may be substituted, this applies to aryl, heteroaryl and heterocyclyl per se as well as to any combined groups containing aryl, heteroaryl or heterocyclyl residues, such as aryl-C1-6-acyl, heteroaryl-C2-4-alkenyl, heterocyclylthio, etc.
The term xe2x80x9cN-oxidesxe2x80x9d means that one or more nitrogen atoms, when present in a compound, are in N-oxide form (Nxe2x86x92O).
The term xe2x80x9cprodrug formsxe2x80x9d means a pharmacologically acceptable derivative, at such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman""s, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
xe2x80x9cAxe2x80x9d in formula I is preferably a C2-8-alkylene chain or a heteroalkylene chain having at least two chain atoms.
More preferably, xe2x80x9cAxe2x80x9d in formula I is a divalent group of the general formula (II): 
wherein
R9, R10, R11 and R12 independently of each other, and independently for each substituted carbon atom, are hydrogen, C1-4-alkyl, trifluoromethyl or oxo;
X is xe2x80x94C(R13)(R14)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94or xe2x80x94N(R15)xe2x80x94;
Y is independently xe2x80x94C(R1-6)(R17)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94or xe2x80x94N(R15)xe2x80x94;
Z is independently xe2x80x94C(R18)(R19)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94N(R15)xe2x80x94;
R13, R14, R16, R17, R18 and R19, independently of each other, and independently for each substituted carbon atom, are hydrogen, C1-4-alkyl or trifluoromethyl or oxo; or two of R13, R14, R16, R17, R18 and R19 together represent an interconnecting bond or an alkylene bridge of 1 to 5 chain carbon atoms or a heteroalkylene bridge of 2 to 5 chain atoms to form, together with the atom(s) to which they are bound, a cyclic structure having 3-8 ring members;
R15 is hydrogen, C1-4-alkyl or C1-6-acyl;
o, p, q and r independently of each other are 0 to 3; and
the four broken lines independently of each other represent an optional carbon-carbon bond;
with the provisos (i) that A does not contain two juxtaposed heteroatoms O or S in an open chain, and (ii) that o, p, q and r together are not more than 8.
The expression xe2x80x9cindependently for each substituted carbon atomxe2x80x9d means that if in formula (II) the integers o and/or Q are 2 or 3, each carbon atom in question may be differently substituted. Thus, in the case of R9 and R10, for example, if o is 2 or 3, for each of the two or three carbons atoms, the meanings of R9 and R10 may be chosen independently of the meanings for R9 and R10 on the other two or three carbon atoms. For example, when o=2, the coupling to X is via a single bond, and R9 and R10 are independently selected from hydrogen and methyl, then e.g. R9 may be hydrogen and R10 methyl on the first carbon atom and both R9 and R10 may be hydrogen on the second carbon atom, i.e. the group 1-methylethylene. If R9 and R10 on the first carbon atom are hydrogen and, on the second carbon atom R9 is hydrogen and R10 is methyl, the group 2-methylethylene is obtained. Exemplary groups for o=3, when R9 and R10 are independently selected from e.g. hydrogen, methyl and oxo, are 2-oxo-1,3-butanediyl, 1-oxo-2-methyl-1,3-propanediyl, 1-oxo-1,3-butanediyl and 1-oxo-2-methyl-1,3-butanediyl. The corresponding applies, of course, also to Y and Z in formula (II) when Y and Z are other than xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and the integers p and r, respectively, are 2 or 3.
When formula (II) contains a carbon-carbon double bond(s) and/or a triple bond(s), one or both substituents on each participating carbon atom is, of course, omitted (for double bonds: R9 and R13 and/or R11 and R16, respectively; and for triple bonds: R9, R10, R13 and R14 and R11, R12, R16 and R17,respectively).
In a preferred embodiment, A in formula (I) is a group xe2x80x94Hetxe2x80x94CH(R6)xe2x80x94CH(R6)xe2x80x94Hetxe2x80x94, where each Het independently is selected from O, S and N(R6), and R6 is as defined above, preferably hydrogen or methyl, particularly hydrogen.
The presently most preferred group A is xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94. Other preferred groups A include xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, and xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
In another preferred embodiment, A is xe2x80x94Oxe2x80x94CH2xe2x80x94 and R is optionally substituted heteroaryl, e.g. 2,3-dihydro-1,4-benzodioxine, 3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1,4-benzoxathiine, quinoline, benzofuran, 3,4-dihydro-2H-pyrido(3,2-b)-1,4-oxazine.
R in formula (I) is preferably optionally substituted aryl or heteroaryl. When R is aryl, it is preferably phenyl which is substituted or unsubstituted, preferably substituted. When R is substituted phenyl, it is preferably substituted in the meta-position. When R is heteroaryl, it is preferably selected from pyridine, isoquinoline, quinoline, quinoxaline, 2,3-dihydro-1,4-benzodioxine, benzoxazole, 2,1,3-benzothiadiazole, coumarin, 3,4-dihydro-2H-1,4-benzoxazine and quinazoline. Especially R is a substituted (especially meta-substituted) phenyl ring, or an unsubstituted or substituted pyridine ring.
Ar in formula (I) is preferably unsubstituted or substituted pyrazine, quinoxaline, 1,2,5-thiadiazole, pyridyl or phenyl.
When Ar is substituted it is usually mono- or (independently) di-substituted. Preferred substituents on Ar are selected from C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulphonyl, cyano, hydroxy, C2-4-alkenyl, C2-4-alkynyl, trifluoromethyl, trifluoromethylthio, halogen, amino, methylamino, dimetylamino, acetamido, aryl, aryloxy, arylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, wherein any aryl and heterocyclyl residues in turn may be substituted in one or more positions independently of each other by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, trifluoromethyl, cyano, hydroxy, amino, methylamino and dimethylamino or acetamido.
R1 in formula (J) is preferably a saturated diazacyclic ring, especially piperazine, unsubstituted or substituted by C1-4-alkyl, e.g. mono-substituted, particularly by methyl (at any position).
The integer n in formula (I) is preferably 0. When n=1, B is preferably xe2x80x94N(R6)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94or xe2x80x94SO2xe2x80x94, where R6 is as defined above.
The integer o in formula (II) is preferably 2.
The integer p in formula (II) is preferably 1.
The integer q in formula (II) is preferably 0.
The integer r in formula (II) is preferably 0.
X, Y and Z are preferably oxygen.
R9 to R12 are preferably hydrogen.
In a preferred subgroup of compounds of formula I, Ar is a pyrazine ring, i.e. compounds of formula (Ia): 
wherein
R20 and R21 independently of each other are hydrogen, C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-acyl, C1-4-alkylsulphonyl, cyano, nitro, hydroxy, C2-4-alkenyl, C2-4-alkynyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, halogen, amino, dimethylamino, methylamino, acetamido, aryl, aryloxy, arylthio, heterocyclyl, heterocyclyloxy or heterocyclylthio, wherein any aryl and heterocyclyl residues in turn may be substituted in one or more positions independently of each other by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, amino, methylamino, dimethylamino or acetamido; or R20 and R21 together with the carbon atoms to which they are bound form a 5- or 6-membered aromatic or heteroaromatic ring, which optionally is independently substituted in one or more positions by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino or acetamido;
m1 and m2 are independently of each other 0 or 1; and
A, B, R, R1 and n are as defined above.
When R20 and R21 in formula (Ia) form a 5- or 6-membered aromatic or heteroaromatic ring together with the pyrazine ring carbons, such a ring may, for example, be selected from the aryl and heteroaryl rings mentioned above.
R20 and R21 are preferably (independently) hydrogen, halogen or methyl. When R20 and R21 form a ring together with the ring carbons to which they are bound, such a ring is preferably benzene (to give quinoxaline) or thiophene (to give thieno[3,4-b]pyrazine). When substituted, the rings are preferably mono- or (independently) disubstituted, such as by halogen or methyl.
The integers m1 and m2 are preferably both zero (i.e. the pyrazine nitrogens are not in oxidized form).
A subgroup of the compounds of formula (Ia) consists of compounds of formula (Ib): 
wherein:
X1 and Y1 independently are xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94or xe2x80x94N(R27)xe2x80x94;
Ra is aryl or heteroaryl optionally substituted as defined for R in claim 1;
R20 and R21 are as defined in claim 11;
R22 is hydrogen, hydroxy, C1-4-alkyl, C3-4-alkenyl, C1-4-acyl, C1-4-alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl or tetrahydropyran-2-yl;
R23 and R24 independently of each other are hydrogen, C1-4-alkyl, hydroxymethyl, C1-4-alkoxymethyl or fluoromethyl;
R25 is hydrogen or C1-4-alkyl;
R26 is hydrogen, C1-4-alkyl or is linked to a carbon atom in Ra adjacent to the atom binding to Y1 to form (together with the carbon atom to which it is bound, Y1 and the two atoms in Ra) a 5- or 6-membered ring which may contain an additional heteroatom,
R27 is hydrogen or C1-4-alkyl, preferably methyl or ethyl; and
y and z independently of each other are 1 or 2.
Exemplary ring systems formed when R26 is linked to Ra are 2,3-dihydro-1,4-benzodioxine, 3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1,4-benzoxathiine and benzofuran.
In formula (Ib), R22 is preferably hydrogen, and R23 and R24 are preferably C1-4-alkyl, especially methyl, or hydrogen. Particularly, R23 is methyl (especially in the 2-position of the piperazine ring; and preferably with (R)-configuration at the chiral carbon atom), z is 1 and R24 is hydrogen. When R23 or R24 are other than hydrogen and at least one of y and z is 2, or y and z both are 1, then R23 or R24, respectively, may be on the same or different carbon atoms.
R25 is preferably hydrogen.
Presently preferred compounds of the general formula (I) above are:
2-(2-Phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-(2-Fluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-(3-Cyanophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-(3-Methoxyhenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-[3-(2-hydroxyethoxy)phenoxy]ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2,3-Dihydro-1,4-benzodioxin-2-ylmethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-(2-Methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-(2,5-Difluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-(3,5-Dimethoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-(3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine
2-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine, particularly the (R)-enantiomer thereof
2-Methyl-1-{3-(2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, particularly the (R)-enantiomer thereof
2-(Quinazolinyl-8-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-(Isoquinolinyl-5-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether
2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-difluoroquinoxaline
2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)thieno[3,4-b]pyrazine
2-(3,4-Dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine
2-Methyl-1-{3-[2-(2-amino-8-quinolinyloxy)ethoxy]-2-pyrazinyl}piperazine, particularly the (R)-enantiomer thereof
1-{3-[2-(2-Methoxy-3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine
2-Methyl-1-{3-[2-(2-methoxy-3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, particularly the (R)-enantiomer thereof,
2-{2-[(2-Chloro-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,
2-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,
1-(3-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, particularly the (R)-enantiomer thereof,
2-(2-{[2-(Methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-3-(1-piperazinyl)pyrazine,
2-Methyl-1-[3-(2-{[2-(methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]piperazine, particularly the (R)-enantiomer thereof,
2-{2-[(2-Bromo-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,
1-(3-{2-[(2-Bromo-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, particularly the (R)-enantiomer thereof,
2-(1-Piperazinyl)-3-(2-{3-[2-(2-pyridinyl)ethoxy]phenoxy}ethoxy)pyrazine,
2-(2-{3-[2-(4-Methyl-1,3-thiazol-5-yl)ethoxy]phenoxy}ethoxy)-3-(1-piperazinyl)pyrazine,
2-(1-Piperazinyl)-3-{2-[3-(tetrahydro-3-furanylmethoxy)phenoxy]ethoxy}pyrazine,
2-(1-Piperazinyl)-3-{2-[3-(tetrahydro-3-furanyloxy)phenoxy]ethoxy}pyrazine,
1-{2-[3-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenoxy]ethyl}2-pyrrolidinone,
2-{2-[3-(2-Methoxyethoxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine,
2-{[3-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenoxy]methyl}-benzonitrile
2-(1-Piperazinyl)-3-{2-[3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]ethoxy}-pyrazine,
N,N-Dimethyl-N-{2-[3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-phenoxy]-ethyl}amine,
7-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2H-chromen-2-one,
1-(3-{2-[(2-Chloro-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, particularly the (R)-enantiomer thereof,
7-Isoquinolinyl 2-{[3-(1-piperazinyl)]-2-pyrazinyl}oxy)ethyl ether,
2-(2-Chloro-4-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,
4-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine,
and their pharmacologically acceptable salts and solvates.
As mentioned above, the compounds of the present invention are useful for the treatment (including prophylactic treatment) of serotonin-related disorders, especially 5-HT2 receptor-related, in a human being or in an animal (including e.g. pets), such as eating disorders, especially obesity; memory disorders, such as Alzheimer""s disease; schizophrenia; mood disorders, including, but not restricted to, major depression and bipolar depression, including both mild and manic bipolar disorder, seasonal affective disorder (SAD); anxiety disorders, including situational anxiety, generalised anxiety disorder, primary anxiety disorders (panic disorders, phobias, obsessive-compulsive disorders, and post-traumatic stress disorders), and secondary anxiety disorders (for example anxiety associated with substance abuse); pain; sexual dysfunctions; and urinary disorders, such as urinary incontinence.
The compounds of the present invention in labelled form, e.g. isotopically labelled, may be used as a diagnostic agent.
The compounds of the general formula (I) above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods.
Method A:
Compounds of formula (I) above in which A is bound to Ar via an O, S or N atom in A, and (i) n=0 and R1 is a saturated aminoazacyclic, aminodiazacyclic, diazacyclic or diazabicyclic residue, or (ii) n=1, B is xe2x80x94N(R6)xe2x80x94or xe2x80x94N(R6)C(R4)(R5)xe2x80x94, wherein R4, R5 and R6 are as defined above, and R1 is a saturated or unsaturated azacyclic, or a saturated azabicyclic, residue, are prepared by reacting a compound of the structural formula (III): 
wherein Ar is as defined above and Hal is halogen, with a compound Rxe2x80x94Axe2x80x2xe2x80x94Xxe2x80x2xe2x80x94H or its corresponding anion where Xxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94or xe2x80x94N(R15)xe2x80x94, Axe2x80x2 is C18-alkylene wherein the carbon chain may be interrupted by one or more heteroatoms and which may have a terminal heteroatom binding to R, said heteroatoms being selected from N, O and S, and R and R15 are as defined above, to produce a compound of the formula (IV): 
wherein Ar, Xxe2x80x2, Axe2x80x2, R and Hal are as defined above. The compound Rxe2x80x94Axe2x80x2xe2x80x94Xxe2x80x2xe2x80x94H may be converted completely or partially to its corresponding anion by treatment with bases, such as triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, K2CO3, NaOH, NaH, KO-t-Bu, lithium diisopropylamide or the like. The reaction is carried out in a solvent, such as dioxane, tetrahydrofuran or N,N-dimethylformamide (DMF), at 0-200xc2x0 C. for 1-24 hours. The compound of formula (IV) is reacted with 1 to 10 molar equivalents of the appropriate amine in a solvent, such as acetonitrile, dioxane, tetrahydrofuran, n-butanol, DMF, or in a mixture of solvents such as DMF/dioxane, optionally in the presence of a base, such as K2CO3, Na2CO3, Cs2CO3, NaOH, triethylamine, pyridine or art the like, at 0-200xc2x0 C. for 1-24 hours to produce the compound of formula (I).
Exemplary amines have the following structures: 
wherein R23, R24, y and z are as defined above, and Z has the meanings defined for R22 in formula (Ib) above or is a suitable protecting group such as tert-butoxycarbonyl, trityl or benzyl.
Method B:
Compounds of formula (I) in which n=1, B is oxygen, sulphur and R1 is a saturated azacyclic or azabicyclic residue, or a group xe2x80x94[C(R4)(R5)]xN(R2a)(R3a), wherein R2, R3, R4, R5 and x are as defined above, are prepared by reacting a compound of formula (IV) above with a corresponding hydroxy- or mercapto-substituted azacyclic or azabicyclic compound, or with a compound HOxe2x80x94R1 or HSxe2x80x94R1, where R1 is xe2x80x94[C(R4)(R5)]xN(R2a)(R3a). Exemplary hydroxy- and mercapto-substituted compounds have the following structures: 
wherein Z is as defined above.
The reaction is carried out in a solvent, such as toluene, DMF or dioxane, in the presence of a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, KOH, KO-t-Bu, NaH or the like, at 0-200xc2x0 C. for 1-24 hours.
Method C:
Compounds of formula (I), wherein A is bound to R via an oxygen or sulphur atom in A, are prepared by reacting a compound of formula (V): 
wherein Ar, R1, B and n are as defined above, Axe2x80x3 is C1-8-alkylene wherein the carbon chain may be interrupted by one or more heteroatoms and which may have a terminal heteroatom bound to Ar, said heteroatoms being selected from N, O and S, and L is a hydroxy, thiol or a leaving group such as, for example, halogen, tosyloxy, mesyloxy and the like, with a compound R-OH or R-SH, where R is as defined above, to produce the compound of formula (I).
When L is a free hydroxy or thiol group, the reaction may be carried out in the presence of diethyl azodicarboxylate (DEAD) or 1,1xe2x80x2-azobis(N,N-dimethylformamide) (cf. Tetrahedron Lett. 1995, 36, 3789-3792), preferably DEAD, and triphenylphosphine (PPh3) in a solvent such as tetrahydrofuran or dichloromethane (Mitsunobu reaction; see Org. React. 1992, 42, 335-656).
When L is a leaving group, the reaction may be carried out in the presence of a 5 suitable base, such as Na2CO3, K2CO3, Cs2CO3, KOH, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or the like, in a solvent, such as acetonitrile or DMF, at 0-200xc2x0 C. for 1-24 hours.
In case the group -(B)nR1 in formula (V) contains a primary or secondary amino group, the nitrogen may be protected with a suitable protecting group, preferably tert-10 butoxycarbonyl, trityl or benzyl. N-Deprotection is then carried out by conventional methods such as those described in Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
Method D:
Compounds of formula (I), in which A is bound to Ar via an O, S or N atom in A, and wherein n=0, or n=1 and B is oxygen, nitrogen, sulphur, xe2x80x94N(R6)C(R4)(R5)xe2x80x94, wherein R4, R5 and R6 are as defined above, are prepared by reacting a compound of formula (III) above with an appropriate amine, or an appropriate hydroxy- or mercapto-substituted compound to produce a compound of formula (VI): 
wherein Ar, B, R1, Hal and n are as defined above. The reaction conditions may be those described for methods A and B above. The compound of formula (VI) is reacted with a compound Rxe2x80x94Axe2x80x2xe2x80x94Xxe2x80x2xe2x80x94H or its corresponding anion, where Xxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R15)-, Axe2x80x2 is C1-8-alkylene wherein the carbon chain may be interrupted by one or more heteroatoms and which may have a terminal heteroatom binding to R, said heteroatoms being selected from N, O and S, and R and R15 are as defined above, to produce a compound of the formula (I).
The reaction conditions may be those described for method A above.
Exemplary amines, hydroxy- and mercapto-substituted compounds include those shown in connection with methods A and B above as well as a compound HOxe2x80x94R1 or HS-R1, where R1 is xe2x80x94[C(R4)(R5)]xN(R2a)(R3a), and wherein R2, R3, R4, R5 and x are as defined above.
Compounds of formula (I), in which Ar represents an optionally substituted phenyl, naphthyl, pyridyl, or quinolinyl nucleus and (i) A is oxygen or (ii) A is bound to Ar via an oxygen atom in A, may be prepared by methods well known in the art, as illustrated in Examples 184 and 185 below.
An obtained compound of formula (I) may be converted to another compound of formula (I) by methods well known in the art (illustrated in e.g. Example 216).
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are maleic acid, fumaric acid, succinic acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, oxalic acid, benzoic acid, hydrochloric acid, sulphuric acid, phosphoric acid, and the like.
The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
The necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds. For example, the aryloxy- and heteroaryloxyethanols used in the preparation of the novel compounds of formula (I) may be prepared using the methods depicted in Scheme 1 below. 
In accordance with the present invention, the compounds of formula (I), in the form of free bases or salts with physiologically acceptable acids, can be brought into suitable galenic forms, such as compositions for oral use, for injection, for nasal spray administration or the like, in accordance with accepted pharmaceutical procedures. Such pharmaceutical compositions according to the invention comprise an effective amount of the compounds of formula (I) in association with compatible pharmaceutically acceptable carrier materials, or diluents, as are well known in the art. The carriers may be any inert material, organic or inorganic, suitable for enteral, percutaneous, subcutaneous or parenteral administration, such as: water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such compositions may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
The compositions according to the invention can e.g. be made up in solid or liquid form for oral administration, such as tablets, pills, capsules, powders, syrups, elixirs, dispersable granules, cachets, suppositories and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, sprays, e.g. a nasal spray, transdermal preparations, e.g. patches, and the like.
As mentioned above, the compounds of the invention may be used for the treatment of serotonin-related disorders in a human being or an animal, such as eating disorders, particularly obesity, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders. The compounds may also be useful for treating gastrointestinal disorders, such as gastrointestinal mobility disorders, e.g. irritable bowel syndrome (IBS), or glaucoma. The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient""s age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.